Major Classes of Analgesics

and their Mechanism of

Action
Emphasis on COX-1 and COX-2 Inhibitors

Analgesics
Analgesics are a group of drugs used to
relieve pain that act in various ways on
the central and peripheral nervous
systems

Inhibitors
An enzyme inhibitor is a molecule that
binds to an enzyme and decreases the
enzymes activity.
The binding of an inhibitor can stop a
substrate from entering the enzyme's
active site and/or hinder the enzyme
from catalyzing its reaction.
Inhibitor binding is either reversible or
irreversible. Irreversible inhibitors usually
react with the enzyme and change it
chemically (e.g. via covalent bond
formation).

Eicosanoids
Class of lipid mediators derived from 20carbon polyunsaturated fatty acids
Involved in local signaling, inflammation,
fever, regulation of blood pressure, blood
clotting, immune system modulation,
control of reproductive processes and
tissue growth, and regulation of the
sleep/wake cycle

Pathways in Biosynthesis of
Eicosanoids from Arachidonic Acid

Prostaglandins
Prostaglandins are the products of the
cyclooxygenase pathway.
Prostaglandins are a subclass of
eicosanoids that mediate local symptoms
of inflammation: vasoconstriction or
vasodilation, coagulation, pain, and fever.
Produced from arachidonic acid by the
cyclooxygenase (COX) enzyme

Prostaglandin Synthesis

COX-1/COX-2
COX-1 is responsible for constitutive
prostaglandin synthesis; involved in pain, renal
function, promoting clotting, and protection of GI
tract
COX-2 is expressed in response to inflammatory
stimuli; involved in the pain produced by
inflammation
The catalytic domain of COX contains the
cyclooxygenase and peroxidase active sites.
The cyclooxygenase and peroxidase activity of
COX-1/COX-2 produces PGH2 from the precursor
fatty acid (arachidonic acid)

Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)
Inhibit production of prostaglandins
Nonselectively inhibit both COX-1, a
constitutive enzyme, and COX-2, which is
induced during the inflammatory
response

Ibuprofen (Advil)
Competitive inhibitor of COX-1 and COX-2
Competes with arachidonic acid for
active site

Aspirin
Irreversible inhibitor of COX-1 and COX-2
Covalently acetylates serine residue 530
preventing AA from reaching the catalytic
site

Pathology

Selectivity for COX-1/COX-2

COX-1 and COX-2 vary only slightly in
their 3-D structure.
Selectivity for COX-1 versus COX-2 is due
to structural difference between the
isoforms.

Selectivity for COX-1/COX-2

Cox-2 Inhibitors (Celecoxib)

Selective inhibitor of COX-2
The polar sulfonamide side chain binds to
the hydrophilic side pocket.

Selectivity for COX-1/COX-2

Pathology

Thank you for your

attention